AntiSm and AntiU1RNP Antibodies

Both anti-Sm and anti-UlRNP are specificities of various components of the spliceosome, which splices pre-messenger RNA. These antibodies consist of RNA-protein complex particles, known as snRNPs (small nuclear ribonuclear proteins): U1-U6 RNA complexes with members of a set of different protein subunits [57]. Sm is associated with U2, U4, and U6 RNA and with the B, B', Dl, D2, D3, E, F, and G polypeptides. Ul snRNP is associated with anti-U1RNP, which is composed of Ul RNA and A, C, or 70-kDa polypeptides.

Anti-Sm antibodies, which were first described by Tan and Kunkel [58], are detected in about 10-25% of Caucasian American lupus patients and in a substantially higher percentage of African American patients [59]. In fact, a recent study of 114 lupus patients (68% African American, 19% Hispanic American, and 13% Caucasian) reported the finding of anti-Sm antibodies in 40% of patients [60]. The presence of anti-Sm antibodies is virtually pathognomonic for lupus. Therefore, they are included in the ACR classification criteria for SLE [22, 23]. There are no particularly strong clinical associations for anti-Sm, but these antibodies have been associated with CNS involvement, nephritis, serosi-tis, oral ulcers, thrombopenia, leukopenia, and pulmonary fibrosis as well as with a lower prevalence of sicca symptoms [61-64]. These associations could not be confirmed in a recent study using a line immunoassay (LIA) for detection of anti-Sm [11]. There is a correlation between SLE disease activity and the anti-Sm level [65].

Anti-U1RNP was first described by Mattioli and Reichlin [66]; it is present in more than 20% of Caucasian Americans with SLE compared to about 40% of African Americans with SLE. Lupus patients with anti-U1RNP autoantibodies tend to have myositis, Raynaud's phenomenon, and arthritis but are less likely to develop lupus nephritis [11, 62, 63, 67]. Since anti-U1RNP antibodies are found in a variety of autoimmune diseases, they are not specific for SLE [68]. High titers of anti-U1RNP are characteristic for mixed connective tissue disease (MCTD); this association was first described by Sharp et al. in 1971 [69].

Nearly all patients with high anti-Sm titers will eventually develop anti-U1RNP antibodies [70]; hence, there is a correlation between the two specificities. The basis for the association is thought to be their coexistence on the same U1 snRNP.

The first epitope in the anti-Sm B/B' system is defined by the peptide PPPGMRPP [71, 72]. No exceptions have yet been identified. This autoimmune response later expands to involve the multiple epitopes on the Sm B/B' antigen in a process referred to as epitope spreading. Immunization with PPPGMRPP results in anti-PPPGMRPP antibody production; the antibodies subsequently bind to different epitopes of the B/B' subunit. Epitope spreading then carries the humoral immune response to the rest of the spliceosome, including A, C, and 70 kDa polypeptides. Some immunized animals also develop anti-dsDNA, thrombocytopenia, seizures, or proteinuria [73, 74].

PPPGMRPP closely resembles PPPGRRP from Epstein-Barr nuclear antigen-1 (EBNA-1); anti-Sm antibodies cross-react with both peptides. This molecular mimicry may partially explain the strong association of Epstein-Barr virus infection with lupus [75-77]. A recent study reported that Epstein-Barr virus in lupus patients was approximately 40 times higher than in controls and that this increase was unrelated to disease activity and immunosuppressant use [78].

Since anti-UlRNP sera can also react, to a variable extent, with B and B' proteins [79], D proteins appear to be the most important Sm antigens. A C-termi-nal SmDl peptide was identified as an important conformational autoantigenic epitope with an extraordinarily high sensitivity and specificity for SLE. Seventy percent of Caucasian SLE sera reacted with this SmDl peptide in ELISA [65]. The sensitivity and specificity of this anti-SmDl (83-119) ELISA was confirmed in other lupus cohorts [80, 81]. Casein added to the blocking buffer in ELISA seems to be an important cofactor in autoantibody reactivity directed against the C-terminal SmD1 (83-119) peptide; it probably functions by changing the conformation of the peptide's critical epitope [82]. This C-terminal SmD1 peptide contains a supercharged GR repeat and shows homology to EBNA-1 [83, 84]. Of note, the anti-SmD1 (83-119) reactivity was significantly higher in anti-dsDNA-positive sera [65]. Immunization of NZB/W Fx mice with this C-terminal SmD1 peptide led to an acceleration of nephritis and stimulated anti-dsDNA production [85]; the peptide was found to generate T-cell help for autoantibodies, including anti-dsDNA [86]. Very recently, our group showed that high-dose tolerance to SmD1 delays the production of autoantibodies, postpones the onset of lupus nephritis (confirmed by histology), and prolongs survival [87]. Tolerance to SmD1 83-119 was adoptively transferred by CD90+ T cells, which reduce T-cell help for autoreactive B cells in vitro. One week after SmD1 83-119 tolerance induction in pre-nephritic mice, we detected cytokine changes in cultures of CD90+ T and B220+ B cells with decreased expression of IFN-gamma and IL-4 and an increase in TGF-beta. Increased frequencies of regulatory IFN-gamma+ and IL10+ CD4+ T cells were later detected. Such regulatory IL-10+/IFN-gamma+ type 1 regulatory T cells prevented autoantibody generation and anti-CD3-in-duced proliferation of naive T cells. These results indicate that SmD1 83-119 peptide may play a dominant role in the activation of helper and regulatory T cells that influence autoantibody generation and murine lupus [88].

Post-translational modifications of the C-terminal SmD1 and SmD3 peptides by dimethylation may play an essential role in the formation of major autoepi-topes [89-91].

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